Phosphatidylinositol 3-kinase/Akt plays a part in tumor necrosis factor-alpha-induced interleukin-6 synthesis in osteoblasts

• Published in: Hormone and metabolic research Vol. 38; no. 9; p. 563
• Main Authors: Takai, S, Tokuda, H, Hanai, Y, Kozawa, O
• Format: Journal Article
• Language: English
• Published: Germany 01.09.2006
• Subjects: Androstadienes - pharmacology; Animals; Cells, Cultured; Chromones - pharmacology; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Flavonoids - pharmacology; Gene Expression Regulation - drug effects; Interleukin-6 - biosynthesis; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Morpholines - pharmacology; Osteoblasts - drug effects; Osteoblasts - enzymology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sirolimus - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 1439-4286
• DOI: 10.1055/s-2006-950502

We previously showed that tumor necrosis factor-alpha (TNF-alpha) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (Akt) is involved in TNF-alpha-stimulated IL-6 synthesis in MC3T3-E1 cells. TNF-alpha induced the phosphorylation of Akt depending upon time. Akt inhibitor, 1L-6-hydroxymethyl-CHIRO-inositol 2-( R)-2- O-methyl-3-O-octadecylcarbonate, significantly suppressed the TNF-alpha-stimulated IL-6 synthesis, but the inhibitory effect was partial. The phosphorylation of Akt induced by TNF-alpha was markedly attenuated by LY294002 and wortmannin, inhibitors of PI3-kinase. Wortmannin and LY294002 significantly reduce the TNF-alpha-induced IL-6 synthesis. On the contrary, the suppressive effects of Akt inhibitor, wortmannin or LY294002 on TNF-alpha-induced phosphorylation of p44/p42 MAP kinase were minor. PD98059, a specific inhibitor of MEK, had little effect on the TNF-alpha-induced phosphorylation of Akt. A combination of Akt inhibitor and PD98059 suppressed the TNF-alpha-induced IL-6 synthesis in an additive manner. These results strongly suggest that PI3-kinase/Akt plays a role in the TNF-alpha-stimulated IL-6 synthesis mainly independent of p44/p42 MAP kinase in osteoblasts.